Summary of Work: The importance of arachidonic acid and linoleic acid metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs reduce the incidence and mortality of colon cancer. These drugs also induce regression of rectal polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAIDs reduce both the size and number of colon tumors induced by carcinogens. Recent studies reported that PGHS-2 is significantly expressed in colon tumors compared to neighboring normal tissue and that mutation in the APC gene is directly linked to the expression of PGHS-2 in the tumors. Thus, prostaglandins play a major role in the development and progression of colon cancer but the mechanism is not clear. Some data suggest effects of prostaglandins are via modulation of apoptosis. We are examining arachidonic and linoleic acid metabolism,and the expression of PGHS-1 and -2, lipoxygenases, and cPLA2 in human cell lines. We observed, in SW-480 and other human colon cells that butyrate-induced differentiation results in an increased expression of PGHS-1 and a lipoxygenase. PGHS-2 expression is high in these cancer cells but expression is not altered by butyrate treatement. Butyrate also induces apoptosis but the addition of PGHS inhibitors did not alter the apoptosis in these cells. We are also using rat intestinal cell lines that highly express PGHS-2 and are used as a model of colon cancer. These studies will further define the potential use of NSAID as chemotherapeutic agents and hopefully better define the role of lipids in colon cancer.